The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

Schmidt, Ewoud R.E.; Kupferman, Justine V.; Stackmann, Michelle; Polleux, Franck

doi:10.1038/s41598-019-54887-4

Cited by 34 publications

(27 citation statements)

References 24 publications

(53 reference statements)

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“…As to HSGDs, a recently discovered example is represented by Notch homolog 2 N -terminal-like ( NOTCH2NL ) gene duplication, producing human-specific NOTCH2 paralog proteins that enhance neural progenitor proliferation [ 157 , 158 , 159 ]. In other studies, SLIT-ROBO Rho GTPase activating protein 2 ( SRGAP2 ) duplications were found to favor human-specific traits of synaptic development, such as protracted synaptic maturation [ 160 , 161 , 162 ]. Another HSGD that is likely involved in neurodevelopment is Rho GTPase activating protein 11B ( ARHGAP11B ), the product of which promotes basal progenitor amplification and neocortex expansion and folding [ 163 , 164 , 165 ].…”

Section: Genomic Sources Of Evolutionary Novelties In the Mammalian Brainmentioning

confidence: 99%

Retrotransposons as Drivers of Mammalian Brain Evolution

Ferrari

Grandi

Tramontano

et al. 2021

Life

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Retrotransposons, a large and diverse class of transposable elements that are still active in humans, represent a remarkable force of genomic innovation underlying mammalian evolution. Among the features distinguishing mammals from all other vertebrates, the presence of a neocortex with a peculiar neuronal organization, composition and connectivity is perhaps the one that, by affecting the cognitive abilities of mammals, contributed mostly to their evolutionary success. Among mammals, hominids and especially humans display an extraordinarily expanded cortical volume, an enrichment of the repertoire of neural cell types and more elaborate patterns of neuronal connectivity. Retrotransposon-derived sequences have recently been implicated in multiple layers of gene regulation in the brain, from transcriptional and post-transcriptional control to both local and large-scale three-dimensional chromatin organization. Accordingly, an increasing variety of neurodevelopmental and neurodegenerative conditions are being recognized to be associated with retrotransposon dysregulation. We review here a large body of recent studies lending support to the idea that retrotransposon-dependent evolutionary novelties were crucial for the emergence of mammalian, primate and human peculiarities of brain morphology and function.

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Section: Genomic Sources Of Evolutionary Novelties In the Mammalian Brainmentioning

confidence: 99%

Retrotransposons as Drivers of Mammalian Brain Evolution

Ferrari

Grandi

Tramontano

et al. 2021

Life

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“…Importantly, such neurodevelopmental disorders are often associated with altered excitatory/inhibitory (E/I) balance, thus when testing the findings of the current study in vivo, it will be important to examine excitatory and inhibitory synapse development in parallel. Interestingly, there are a number of potential molecular targets that are thought to both limit glutamatergic synapse formation and regulate E/I balance, such as the SRGAP2s (Fossati et al, 2016;Schmidt et al, 2019) and the activity-regulated MEF2C (Harrington et al, 2016). These potential mechanisms should be investigated as the role of depolarizing GABA A transmission in synapse formation continues to be more finely dissected.…”

Section: Depolarizing Gaba a Transmission And Sustained Changes In Glmentioning

confidence: 99%

Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit

Salmon

Pribiag

Gizowski

et al. 2020

Front. Cell. Neurosci.

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γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the mature brain but has the paradoxical property of depolarizing neurons during early development. Depolarization provided by GABA A transmission during this early phase regulates neural stem cell proliferation, neural migration, neurite outgrowth, synapse formation, and circuit refinement, making GABA a key factor in neural circuit development. Importantly, depending on the context, depolarizing GABA A transmission can either drive neural activity or inhibit it through shunting inhibition. The varying roles of depolarizing GABA A transmission during development, and its ability to both drive and inhibit neural activity, makes it a difficult developmental cue to study. This is particularly true in the later stages of development when the majority of synapses form and GABA A transmission switches from depolarizing to hyperpolarizing. Here, we addressed the importance of depolarizing but inhibitory (or shunting) GABA A transmission in glutamatergic synapse formation in hippocampal CA1 pyramidal neurons. We first showed that the developmental depolarizing-to-hyperpolarizing switch in GABA A transmission is recapitulated in organotypic hippocampal slice cultures. Based on the expression profile of K + −Cl − co-transporter 2 (KCC2) and changes in the GABA reversal potential, we pinpointed the timing of the switch from depolarizing to hyperpolarizing GABA A transmission in CA1 neurons. We found that blocking depolarizing but shunting GABA A transmission increased excitatory synapse number and strength, indicating that depolarizing GABA A transmission can restrain glutamatergic synapse formation. The increase in glutamatergic synapses was activity-dependent but independent of BDNF signaling. Importantly, the elevated number of synapses was stable for more than a week after GABA A inhibitors were washed out. Together these findings point to the ability of immature GABAergic transmission to restrain glutamatergic synapse formation and suggest an unexpected role for depolarizing GABA A transmission in shaping excitatory connectivity during neural circuit development.

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“…When expressed in mouse cortical pyramidal neurons (PNs) in vivo, SRGAP2C inhibits the function of its ancestral copy SRGAP2A, resulting in changes in synaptic development mimicking those characterizing human cortical PNs. These include an increase in the density of both excitatory and inhibitory synapses received by layer 2/3 PNs, and neotenic features of excitatory and inhibitory synaptic development (Charrier et al, 2012;Fossati et al, 2016;Schmidt et al, 2019). These findings indicated that mouse cortical PNs humanized for SRGAP2C expression receive an increased number of synaptic inputs, similar to what is observed in humans (Benavides-Piccione et al, 2003;Elston et al, 2001).…”

Section: Introductionmentioning

confidence: 67%

A human-specific modifier of cortical circuit connectivity and function improves behavioral performance

Schmidt

Zhao

Park

et al. 2019

Preprint

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The remarkable cognitive abilities characterizing humans has been linked to unique patterns of connectivity characterizing the neocortex. Comparative studies have shown that human cortical pyramidal neurons (PN) receive a significant increase of synaptic inputs when compared to other mammals, including non-human primates and rodents 1-4 , but how this may relate to changes in cortical connectivity and function remains largely unknown. We previously identified a human-specific gene duplication (HSGD), SRGAP2C, that, when induced in mouse cortical PNs drives human-specific features of synaptic development, including a correlated increase in excitatory (E) and inhibitory (I) synapse density 5,6 . However, the origin and nature of this increased connectivity and its impact on cortical circuit function was unknown. Here, using a combination of transgenic approaches and quantitative monosynaptic tracing, we demonstrate that humanization of SRGAP2C expression in the mouse cortex leads to a specific increase in local and longrange cortico-cortical inputs received by layer 2/3 cortical PNs. Moreover, using in vivo 2photon imaging in the barrel cortex of awake mice, we show that humanization of SRGAP2C expression increases the reliability and selectivity of sensory-evoked responses in layer 2/3 PNs. Our results suggest that the emergence of SRGAP2C during human evolution led to increased local and long-range cortico-cortical connectivity and improved reliability of sensory-evoked cortical coding.Recent studies have led to the identification of some of the genomic mechanisms and corresponding cellular and molecular substrates underlying human brain evolution. For example, during human brain development, prolonged neurogenesis and the expansion of a specific class of neural progenitors, the outer radial glia (oRG), have been proposed to lead to higher neuronal production, in particular of supragranular layer 2/3 PNs 7-10 . However, besides the tangential expansion of the cortex, human brain evolution has critically relied on changes in neuronal connectivity [1][2][3][4]11 , for which the genetic, cellular and molecular substrates remain largely unknown.We previously identified a specific HSGD affecting Slit-Robo GTPase Activating Protein 2A (SRGAP2A) which led to the emergence of the human-specific paralog SRGAP2C 5,6 . When expressed in mouse cortical pyramidal neurons (PNs) in vivo, SRGAP2C inhibits the function of

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The human-specific paralogs SRGAP2B and SRGAP2C differentially modulate SRGAP2A-dependent synaptic development

Cited by 34 publications

References 24 publications

Retrotransposons as Drivers of Mammalian Brain Evolution

Retrotransposons as Drivers of Mammalian Brain Evolution

Depolarizing GABA Transmission Restrains Activity-Dependent Glutamatergic Synapse Formation in the Developing Hippocampal Circuit

A human-specific modifier of cortical circuit connectivity and function improves behavioral performance

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